Cholesterol Molecules Alter the Energy Landscape of Small Aβ1–42 Oligomers

Ngo, Son Tung; Nguyen, Phuong H.; Derreumaux, Philippe

doi:10.1021/acs.jpcb.1c00036

Cited by 15 publications

(20 citation statements)

References 70 publications

(135 reference statements)

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“…This phenomenon is affected by specific lipids including cholesterol, sphingomyelin, and gangliosides [717,718]: lipid types typically present in the outer leaflet of the cell membrane. Amyloid fibers at a membrane surface have thus been frequently studied using MD simulations, e.g., [719][720][721][722][723][724][725][726][727][728][729][730], however, a surprisingly small fraction of this work has been performed in the context of drug design [731,732]. Khondker et al, proposed designing drugs with a mode of action that involved modulating membrane properties to affect the aggregation of amyloid-β25-35 at the bilayer surface [229].…”

Section: Can Drugs Prevent Amyloid Formation Via the Modification Of Membrane Properties?mentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Can Drugs Prevent Amyloid Formation Via the Modification Of Membrane Properties?mentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…Furthermore, the simulations show that dimer formation on membranes with Chol inside occur almost 2X faster than on a similar membrane without Chol [ 12 ]. The effect of Chol on the free energy and conformational sampling has also been reported for Aβ dimers and trimers [ 32 ]. In addition to significant changes to the FEL, the authors also report that presence of Chol induces greater β-structure content in the dimers and trimers of the Aβ(1-42); they also report that dimer to trimer change in β-structure is also significant when Chol is present, going from 26% to 41% [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…The effect of Chol on the free energy and conformational sampling has also been reported for Aβ dimers and trimers [ 32 ]. In addition to significant changes to the FEL, the authors also report that presence of Chol induces greater β-structure content in the dimers and trimers of the Aβ(1-42); they also report that dimer to trimer change in β-structure is also significant when Chol is present, going from 26% to 41% [ 32 ]. The discrepancy in fraction of β-structure secondary structure between monomer and oligomers can be explained by data obtained by Ono et al, in which different pure oligomers of defined sizes were compared [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration

Hashemi

Banerjee

Lyubchenko

2022

IJMS

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The effects of membranes on the early-stage aggregation of amyloid β (Aβ) have come to light as potential mechanisms by which neurotoxic species are formed in Alzheimer’s disease. We have shown that direct Aβ-membrane interactions dramatically enhance the Aβ aggregation, allowing for oligomer assembly at physiologically low concentrations of the monomer. Membrane composition is also a crucial factor in this process. Our results showed that apart from phospholipids composition, cholesterol in membranes significantly enhances the aggregation kinetics. It has been reported that free cholesterol is present in plaques. Here we report that free cholesterol, along with its presence inside the membrane, further accelerate the aggregation process by producing aggregates more rapidly and of significantly larger sizes. These aggregates, which are formed on the lipid bilayer, are able to dissociate from the surface and accumulate in the bulk solution; the presence of free cholesterol accelerates this dissociation as well. All-atom molecular dynamics simulations show that cholesterol binds Aβ monomers and significantly changes the conformational sampling of Aβ monomer; more than doubling the fraction of low-energy conformations compared to those in the absence of cholesterol, which can contribute to the aggregation process. The results indicate that Aβ-lipid interaction is an important factor in the disease prone amyloid assembly process.

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“…30 Atomistic simulations emerge as appropriate methods for evaluating the structural changes and interactions between biomolecules. 35,36 Therefore, in this work, a fragment of NAb bind to 501Y.V2/wildtype (WT) S proteins were revealed using molecular dynamics (MD) and steered-MD (SMD) simulations. Furthermore, the obtained results indicated that 501Y.V2 complex is less stable compared with the WT one.…”

Section: Studyingmentioning

confidence: 99%

501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

Ngo

2021

Preprint

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<div> <p><a>SARS-CoV-2 Spike (S) protein is a major biological target for COVID-19 vaccine design. Unfortunately, recent reports indicated that Spike (S) protein mutations can lead to antibody resistance. </a>However, understanding the process is limited, especially at the atomic scale. The structural change of S protein and neutralizing antibody fragment (FAb) complexes was thus probed using molecular dynamics (MD) simulations. In particular, backbone RMSD of the 501Y.V2 complex was significantly larger than that of the WT implying a large structural change of the mutation system. Moreover, the mean of , CCS, and SASA are almost the same when compared two complexes, but the distribution of these values are absolutely different. Furthermore, the free energy landscape of the complexes was significantly changed when the 501Y.V2 variant was induced. The binding pose between S protein and FAb was thus altered. The FAb-binding affinity to S protein was thus reduced due to revealing over steered-MD (SMD) simulations. The observation is in good agreement with the respective experiment that the 501Y.V2 SARS-CoV-2 variant can escape from neutralizing antibody (NAb).</p> </div>

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Cholesterol Molecules Alter the Energy Landscape of Small Aβ1–42 Oligomers

Cited by 15 publications

References 70 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration

501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

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